1. Field of the Invention
This invention relates to new agents which inhibit renal dehydropeptidase (DHP) and, therefore, potentiate the antibiotic activity of carbapenem antibiotics.
2. Brief Description of the Art
Renal dehydropeptidase (E.C. 3.4.13.11) is a mammalian enzyme which metabolizes carbapenem antibiotics such as thienamycin and imipenem. Inhibition of this enzyme enhances the urinary recovery of these antibiotics and reduces their renal toxicity. EPO Publication No. 0091594 to Sanraku-Ocean Co., Ltd. describes aminocarboxylic acid derivatives possessing dipeptidase inhibiting activity. EPO Publication No. 0210545 to Merck & Co., Inc. describes renin inhibitors which are phosphinic acids similar to the instant compounds where R.sub.1 is cyclohexylmethyl. The development of cilastatin as a renal dehydropeptidase inhibitor for use in combination with imipenem has been reviewed by F. M. Kahan et al., J. Antimicrobial Chemotherapy, 12, Suppl. D, 1-35 (1983).
U.S. Pat. No. 4,374,131 to Petrillo (assigned to E.R. Squibb & Sons, Inc.) discloses amino and substituted amino phosphinyl-alkanoyl compounds which are useful hypertensive agents due to their angiotensin-converting-enzyme (ACE) inhibition activity.
E. D. Thorsett et al., (Merck & Co., Inc.) Proc. Natl. Acad. Sci. USA Vol. 79, pp 2176-2180 (April 1982) discloses phosphorus containing inhibitors of angiotensin-converting enzyme.
Further, U.S. Pat. No. 4,715,994 by Parsons et al., (assigned to Merck & Co., Inc.) discloses 3-(1-aminoalkyl-propionic)-(2-substituted) phosphinic acids which display antibacterial activity and potentiate carbapenem antibiotics.
With this background, the search for newer and more effective antibacterial agents is a continuing one.